WO2011153815A1 - 唾液酸(α-(2→6))-D-吡喃糖衍生物及其合成方法和应用 - Google Patents
唾液酸(α-(2→6))-D-吡喃糖衍生物及其合成方法和应用 Download PDFInfo
- Publication number
- WO2011153815A1 WO2011153815A1 PCT/CN2011/000610 CN2011000610W WO2011153815A1 WO 2011153815 A1 WO2011153815 A1 WO 2011153815A1 CN 2011000610 W CN2011000610 W CN 2011000610W WO 2011153815 A1 WO2011153815 A1 WO 2011153815A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- group
- acid
- nhc
- klh
- Prior art date
Links
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 title claims abstract description 17
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 229920001184 polypeptide Polymers 0.000 claims abstract description 22
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 22
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 22
- 229960005486 vaccine Drugs 0.000 claims abstract description 13
- 102000014914 Carrier Proteins Human genes 0.000 claims abstract description 7
- 108010078791 Carrier Proteins Proteins 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- -1 β-galactosyl Chemical group 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 8
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 150000002016 disaccharides Chemical class 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- 108090000623 proteins and genes Proteins 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 5
- VOYQYHZKXRAELV-UHFFFAOYSA-N decyl 2,2,2-trifluoroacetate Chemical compound CCCCCCCCCCOC(=O)C(F)(F)F VOYQYHZKXRAELV-UHFFFAOYSA-N 0.000 claims description 5
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 claims description 5
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims description 5
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 125000003172 aldehyde group Chemical group 0.000 claims description 4
- ZMLAQDPXQKQOGC-UHFFFAOYSA-N decyl 2,2-dichloroacetate Chemical compound CCCCCCCCCCOC(=O)C(Cl)Cl ZMLAQDPXQKQOGC-UHFFFAOYSA-N 0.000 claims description 4
- HPEZNVUNNHOIHK-UHFFFAOYSA-N decyl 2-fluoroacetate Chemical compound CCCCCCCCCCOC(=O)CF HPEZNVUNNHOIHK-UHFFFAOYSA-N 0.000 claims description 4
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- DPDWSCSZSJXRRU-UHFFFAOYSA-N decyl 2,2-difluoroacetate Chemical compound FC(C(=O)OCCCCCCCCCC)F DPDWSCSZSJXRRU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 230000001268 conjugating effect Effects 0.000 claims description 2
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 229960005215 dichloroacetic acid Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 102000003886 Glycoproteins Human genes 0.000 abstract description 11
- 108090000288 Glycoproteins Proteins 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 3
- 239000008103 glucose Substances 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 abstract 1
- 102000002068 Glycopeptides Human genes 0.000 abstract 1
- 108010015899 Glycopeptides Proteins 0.000 abstract 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 230000015572 biosynthetic process Effects 0.000 description 65
- 238000003786 synthesis reaction Methods 0.000 description 65
- 239000011734 sodium Substances 0.000 description 45
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 22
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 19
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 230000003053 immunization Effects 0.000 description 15
- 238000002649 immunization Methods 0.000 description 15
- 210000002966 serum Anatomy 0.000 description 14
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 13
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 229940126543 compound 14 Drugs 0.000 description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 8
- 150000001720 carbohydrates Chemical class 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 229930182558 Sterol Natural products 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000003432 sterols Chemical class 0.000 description 6
- 235000003702 sterols Nutrition 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 4
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 229940127007 Compound 39 Drugs 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 101000707241 Homo sapiens Seven in absentia homolog 3 Proteins 0.000 description 3
- 102100031749 Seven in absentia homolog 3 Human genes 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 241001669573 Galeorhinus galeus Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 2
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 2
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000011102 Thera Species 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 229940125900 compound 59 Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- CSSYKHYGURSRAZ-UHFFFAOYSA-N methyl 2,2-difluoroacetate Chemical compound COC(=O)C(F)F CSSYKHYGURSRAZ-UHFFFAOYSA-N 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- FOYWCEUVVIHJKD-UHFFFAOYSA-N 2-methyl-5-(1h-pyrazol-5-yl)pyridine Chemical compound C1=NC(C)=CC=C1C1=CC=NN1 FOYWCEUVVIHJKD-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- CZOGCRVBCLRHQJ-WHWAGLCYSA-N N-acetyl-alpha-neuraminyl-(2->6)-N-acetyl-alpha-D-galactosamine Chemical compound O[C@@H]1[C@H](O)[C@@H](NC(=O)C)[C@@H](O)O[C@@H]1CO[C@@]1(C(O)=O)O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C1 CZOGCRVBCLRHQJ-WHWAGLCYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- NKVNXNUKNLEVGM-VDBPQNRRSA-N O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC1[C@H](N)[C@@H](O)[C@@H](O)[C@H](O1)CO Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC1[C@H](N)[C@@H](O)[C@@H](O)[C@H](O1)CO NKVNXNUKNLEVGM-VDBPQNRRSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- JVOWHDCGJSEUMO-UHFFFAOYSA-N decyl 2,2,2-trichloroacetate Chemical compound CCCCCCCCCCOC(=O)C(Cl)(Cl)Cl JVOWHDCGJSEUMO-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- VHFUHRXYRYWELT-UHFFFAOYSA-N methyl 2,2,2-trichloroacetate Chemical compound COC(=O)C(Cl)(Cl)Cl VHFUHRXYRYWELT-UHFFFAOYSA-N 0.000 description 1
- HKMLRUAPIDAGIE-UHFFFAOYSA-N methyl 2,2-dichloroacetate Chemical compound COC(=O)C(Cl)Cl HKMLRUAPIDAGIE-UHFFFAOYSA-N 0.000 description 1
- RJBYSQHLLIHSLT-UHFFFAOYSA-N methyl 2-fluoroacetate Chemical compound COC(=O)CF RJBYSQHLLIHSLT-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
- C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
- A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
Definitions
- the present invention relates to a saccharide conjugate, and more particularly to a sialic acid (cc - (2 ⁇ 6) ) - D-aminopyranose derivative and a conjugate formed from the derivative with a protein or a polypeptide, and the above compound
- the present invention also relates to the use of these compounds in the preparation of antitumor drugs, and belongs to the field of antitumor saccharide vaccines. Background technique
- anti-tumor vaccines based on carbohydrate antigens have become a research hotspot (Keding, S. Carbohydrate vaccines. Chem. Eng. News. 2004, 82, 31-35.).
- the antigen STn is a disaccharide structure containing sialic acid, which is expressed in human breast cancer, colorectal cancer, ovarian cancer, prostate cancer, and rarely expressed in normal tissues (Holmberg, L. Expert Rev. Vaccines 2004, 3, 655-663. ), thus becoming an important point in tumor immunotherapy.
- Biomira Canada developed the STn-KLH (keyhole limpet hemocyanin) conjugate Theratope® (later acquired by Merk) for the prevention of colorectal cancer and breast cancer metastasis.
- STn-KLH keyhole limpet hemocyanin conjugate Theratope®
- Thera tope® alone did not improve disease progression time and overall survival, but only when combined with hormones, can improve disease progression time by 5.8 hormones alone.
- the month increased to 8.3 months. Since the antitumor activity of Theratope® is dependent on the presence of hormones, its antitumor activity is compromised (Holmberg, L. Expert Rev. Vaccines 2004, 3, 655-663.).
- Theratope® Similar to the difficulties encountered with Theratope®, the common problem with anti-tumor glucose vaccines today is that vaccines do not produce a satisfactory immune response in vivo.
- the most common method currently used is to couple sugar antigens to carrier proteins, but One method is not very effective for tumor antigens, and Theratope® is one such example. Summary of the invention
- the first technical problem to be solved by the present invention is to overcome the defects of low immunological activity commonly existing in anti-tumor saccharide vaccines, and to provide new tumor-associated saccharide antigen-modifying substances, thereby providing a kind of sugar having better activity for tumor treatment- Protein (polypeptide) conjugate.
- Another technical problem to be solved by the present invention is to provide a method of synthesizing the above saccharide-protein (polypeptide) conjugate.
- the technical problem to be solved by the present invention is achieved by the following technical solutions:
- the present invention first provides a sialic acid ( ct - (2 ⁇ 6) ) - D-aminopyranose derivative, the structural formula of which is represented by the formula (I):
- R (e) selected from the group consisting of an amide group, -NH 2 , - ⁇ or - OH; preferably, the amide group is selected from -NH C (0) CH x C l y ,
- - NHC (0) C3 ⁇ 4F y -NHC (0) CH,Br y , -NHC (0) H , - NHC (0) C a H 2a+1 , — NHC (0) C a H 2a 0H , - NHC (0) C b H 2b-1 , -NHC (0) C b H 2b — 3 ; wherein x or y is selected from 0, 1, 2 or 3, and x+y is equal to 3; a is selected from 1 to 20 Any integer in the formula; b is selected from any of 2 to 20;
- R 2 is selected from the group consisting of an amide group, -NH 2 , -N 3 or -OH; preferably, the amide group is selected from -NH C (0) CH p C l q , — NHC (0) CH P F , - NHC (0) CH p Br q , — NHC (0) H , — NHC (0) C a H 2a+1 , — NHC (0) C a H 2a 0H , - NHC (0) C b H 2b-1 , -NHC (0) C b H 2b-3 ; wherein p or q is selected from 0, 1, 2 or 3, and p + q is equal to 3; a is selected from any of 1 to 20; b is selected from 2 Any integer up to 20;
- R 3 is selected from -C0 2 H, -CH 2 0H, -C0 2 M, -C(0)NHOH or hydrogen, wherein M is an alkyl group, an aryl group or a heterocyclic ring; 3 has a spatial orientation of a flat bond or an upright key;
- R 4 is selected from a substituent having a double bond, an acetylenic bond, an azide, an aldehyde group, a protective acetal, a maleimide group, a fluorenyl group, a protective sulfhydryl group, a seleno group, a protected seleno group, - 13 ⁇ 4 or -0NH 2
- R 4 is an allyl group
- R 5 is 0H, and its spatial orientation is an upright key or a flat key
- R 6 is selected from hydrogen or ⁇ -galactosyl
- a glycoprotein (polypeptide) conjugate is obtained by conjugating a compound represented by the formula (I) to a polypeptide or a protein.
- a compound represented by the formula (I) to a polypeptide or a protein.
- base addition salts of the compounds of the invention may be prepared, and such salts are included in the present invention.
- the base addition salt of the compound of the present invention is preferably pharmaceutically acceptable, forming a non-toxic salt with a suitable base (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, aqueous ammonia), in addition to a pharmaceutically acceptable salt, other salts Also included in the present invention.
- a suitable base e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, aqueous ammonia
- the glycoprotein (polypeptide) conjugate of the present invention as an antitumor vaccine produces a strong immune response in mice, and the titer of the glycoprotein (polypeptide) conjugate antibody of the present invention is increased as compared with Thera tope®. Between 3 and 20 times, the ratio of IgG/I gM has also increased by a factor of 2 to 14.
- Another technical problem to be solved by the present invention is to provide a process for producing a compound represented by the following formula (I).
- the compound is used as a raw material, and is subjected to an acylation reaction with a hydrazine, a carboxylic acid or a carboxylic acid ester in a solvent under the action of a reaction assistant to obtain a disaccharide compound having a structure represented by the formula (I).
- the starting material comprises allyl 4- 0-(5-amino-3,5-dideoxypyranylneuraminyl)-2-acetamido-2-deoxy- ⁇ - ⁇ pyran Glycoside, allyl 4-0 ⁇ (5-acetylamino-3,5-dideoxy- ⁇ - ⁇ pyranyl-neuraminyl)-2-amino-2-deoxy- ⁇ - ⁇ pyran Lactosyl or allyl (5-amino-3, 5-dideoxy- ⁇ - ⁇ ""pyranyl-neuraminic acid”-2-amino-2-deoxy- ⁇ - ⁇ -galactopyranoside;
- the acid anhydride includes an acid anhydride of a fatty acid, and the aliphatic chain may have a substituent of a fluorine atom or a chlorine atom; preferably, the acid anhydride includes acetic anhydride, propionic anhydride, n-butyric anhydride, isobutyric anhydr
- the reaction auxiliary agent may be an organic base or an inorganic base
- the solvent may be water or an organic solvent.
- Still another technical problem to be solved by the present invention is to provide a method of synthesizing a glycoprotein (polypeptide) conjugate, comprising:
- the present invention synthesizes sialic acid (ot - (2 ⁇ 6) ) -D-aminopyranose derivative represented by formula (I) using D-galactosamine (glucose) and sialic acid as raw materials, and Coupling with a carrier protein or polypeptide yields a glycoprotein (polypeptide) conjugate.
- the structure of the compound of the present invention uses a derivatized acyl group instead of an acetyl group, has a novel structure, and exhibits excellent activity in an antitumor vaccine.
- Mouse experiments have shown that, by structure-derived, saccharide-based vaccines produce more efficient immune responses, producing more antibodies, and IgG/IgM is also evident.
- STn antigen is expressed on a variety of tumors, such as human breast cancer, colorectal cancer, ovarian cancer, prostate cancer, the scope of application of the present invention is broad.
- Fig. 1 shows the structural formula of the N-acyl modified sialic acid ( ⁇ -(2 ⁇ 6))-D-aminopyranose derivative of the present invention.
- Figure 2 is a molecular structural formula of the compounds 1-42 and 61-64 of the present invention.
- Figure 3 shows the structure of the compound 43-60 of the present invention and the synthetic route of some of the compounds
- Figure 4 is a synthetic route diagram of compounds 60 and 53.
- Figure 5 N acylation route of the invention; i) the corresponding anhydride, MeOH, NaHC0 3 ; or ii) the corresponding oxime ester, TEA, MeOH; or iii) the corresponding carboxylic acid, HBTU, DMF.
- Example 1 Synthesis of Compound 2
- Compound 48 (for its synthesis, see Example 42) (100 mg, 0.119 mmol) was dissolved in 10 mL of methanol, and NaOMe/MeOH solution (30%, 0.02 g, 0.11 mmol) was added and stirred at room temperature for 0.5 hour. After the reaction system was adjusted to pH 3 with 1N HCl / MeOH, the mixture was concentrated in vacuo. The primary product was passed through a P-2 column and eluted with water. Get pure. The yield was 95%.
- Compound 14 is used as raw material (10-15 mg, 0.02-0.03 mmol), and HBTU (benzotriazole-oxime, hydrazine, ⁇ ', ⁇ '-tetradecylurea hexafluorophosphate) (each amino group 1) 3 equivalents of HBTU), monochloroacetic acid (2-4 equivalents of monochloroacetic acid per amino group) Dissolved in 2 mL of DMF under nitrogen and stirred at room temperature. Further add DIPEA (N, N-diisopropylethylamine) (13 equivalents to the starting material), the reaction is detected by TLC until the starting material is completely consumed (generally 1-4 hours).
- DIPEA N, N-diisopropylethylamine
- Compound 39 (the preparation method is shown in Example 38) (18.0 rag, 0.032 mmol) was dissolved in 5 mL of methanol, and 50% aqueous NH 2 0H (0.5 raL, 7.57 mmol) and KCN (1.0 mg, 0.016 raraol) were added. Stir at room temperature for 20 hours. The reaction solution was concentrated under vacuum, and the residue was passed through a C18 column, and then passed to a column, and eluted with water. Get pure. The yield was 50%.
- Compound 48 (the preparation method is shown in Example 42) (100 mg, 0.119 mmol) was dissolved in 10 mL of methanol, and NaOMe/MeOH solution (30%, 0.02 g, 0.11 mmol) was added and stirred at room temperature for 4 hours. After the reaction system was adjusted to pH 6 with IN HCl / MeOH, the mixture was concentrated in vacuo. The primary product was passed through a C18 column and the water/sterol eluted. Get pure. Yield 95%.
- the hapten (Compound 2, 10 mg) was dissolved in 2 ml of anhydrous methanol, and ozone-containing air was introduced at 72 ° C. When the system turned blue (about 10-30 minutes), the ozone was stopped. After 10 minutes, the system is still blue. Nitrogen gas was introduced into the reaction system for about 10 minutes to remove excess ozone. 0.5 ml of ruthenium ketone was added dropwise, and then the temperature of the reaction system was naturally raised to room temperature. After 2 hours, the solvent was removed under vacuum to obtain a hapten containing an aldehyde group.
- glycoprotein conjugate STn-KLH was obtained.
- the compounds 3-14, 16-24, 29-34, 42 prepared in Examples 3-47 of the present invention are coupled with a carrier protein (polypeptide) to obtain respective protein (polypeptide) conjugates.
- a carrier protein polypeptide
- the compounds 3-14, 16-24, 29-34, 42 prepared in Examples 3-47 of the present invention are coupled with a carrier protein (polypeptide) to obtain respective protein (polypeptide) conjugates.
- a carrier protein polypeptide
- Test compound glycoprotein (polypeptide) conjugate prepared in Example 49 of the present invention.
- the titer of the mixed serum of each group of mice, and the serum titer of each mouse of the conjugates of 20, 31 and 21 were detected by ELISA.
- washing and blocking Add 200 ul of washing buffer PBS-Tween20 (0.05%) to each well, wash the plate, wash 3 times, then add 200 ul of blocking solution (3% BSA-PBS) per well, 37 °C, 1 hour.
- Antibody titer against STn in mouse serum was determined 13 days after the third immunization IgG IgM immunized with STn-KLH 50, 144 5763 immunized with 3-KLH ⁇ 2500 ⁇ 1000 immunized with 4-KLH 17, 040 1604 immunized With 5-KLH 38, 878 1872 immunized with 6-KLH ⁇ 2500 ⁇ 1000 immunized with 7-KLH 23, 279 4706 immunized with 8-KLH 43, 201 4963 immunized with 9-KLH 4714 2897 immunized with 10-KLH 55, 004 ⁇ 1000 immunized with 11- LH 4054 ⁇ 1000 immunized with 12-KLH 11, 783 ⁇ 1000 immunized with 13-KLH 24, 12 ⁇ 1000 immunized with 14-KLH ⁇ 2500 ⁇ 1000 immunized with 16-KLH ⁇ 2500 2571 immunized with 17
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Crystallography & Structural Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Analytical Chemistry (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11791807.8A EP2581380B1 (en) | 2010-06-09 | 2011-04-08 | SIALIC ACID (alpha-(2-6))-D-AMINOPYRANOSE DERIVATIVES, SYNTHESIS METHODS AND USES THEREOF |
US13/703,007 US9695208B2 (en) | 2010-06-09 | 2011-04-08 | Sialic acid (A-(2-6))-D-aminopyranose derivatives, synthesis methods and uses thereof |
JP2013512727A JP5815687B2 (ja) | 2010-06-09 | 2011-04-08 | シアル酸(α−(2→6))−D−ピラノース誘導体及びその合成方法と応用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201010202388.5A CN102276662B (zh) | 2010-06-09 | 2010-06-09 | 唾液酸(α-(2→6))-D-吡喃糖衍生物及其合成方法和应用 |
CN201010202388.5 | 2010-06-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011153815A1 true WO2011153815A1 (zh) | 2011-12-15 |
Family
ID=45097495
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2011/000610 WO2011153815A1 (zh) | 2010-06-09 | 2011-04-08 | 唾液酸(α-(2→6))-D-吡喃糖衍生物及其合成方法和应用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US9695208B2 (ja) |
EP (1) | EP2581380B1 (ja) |
JP (1) | JP5815687B2 (ja) |
CN (1) | CN102276662B (ja) |
WO (1) | WO2011153815A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554198B (zh) * | 2013-10-21 | 2016-05-18 | 中国科学院微生物研究所 | 流感病毒唾液酸寡糖功能受体及其合成方法 |
CN110064050B (zh) * | 2019-04-29 | 2020-10-02 | 北京大学 | 含STn或F-STn的糖缀合物及其制备方法和在抗肿瘤疫苗中的应用 |
CN111875649B (zh) * | 2020-07-20 | 2021-12-17 | 广州中医药大学(广州中医药研究院) | 一种海藻糖衍生物与糖抗原的缀合物及其制备方法与应用 |
CN115521348A (zh) * | 2022-10-12 | 2022-12-27 | 北京大学 | 唾液酸(α-(2→6))-D-氨基吡喃半乳糖衍生物或其盐、糖缀合物及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995029927A2 (en) * | 1994-05-02 | 1995-11-09 | Biomira, Inc. | Process for preparation of glycosides of tumor-associated carbohydrate antigens |
CN1543350A (zh) * | 2001-08-14 | 2004-11-03 | 糖半抗原和聚集的蛋白载体的免疫原性结合物 | |
US20090324619A1 (en) * | 2008-06-27 | 2009-12-31 | Academia Sinica | Immunogenic Protein Carrier Containing An Antigen Presenting Cell Binding Domain and A Cysteine-Rich Domain |
-
2010
- 2010-06-09 CN CN201010202388.5A patent/CN102276662B/zh active Active
-
2011
- 2011-04-08 JP JP2013512727A patent/JP5815687B2/ja active Active
- 2011-04-08 EP EP11791807.8A patent/EP2581380B1/en active Active
- 2011-04-08 WO PCT/CN2011/000610 patent/WO2011153815A1/zh active Application Filing
- 2011-04-08 US US13/703,007 patent/US9695208B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995029927A2 (en) * | 1994-05-02 | 1995-11-09 | Biomira, Inc. | Process for preparation of glycosides of tumor-associated carbohydrate antigens |
US6013779A (en) | 1994-05-02 | 2000-01-11 | Biomira, Inc. | Process for preparation of glycosides of tumor-associated carbohydrate antigens |
CN1543350A (zh) * | 2001-08-14 | 2004-11-03 | 糖半抗原和聚集的蛋白载体的免疫原性结合物 | |
US20090324619A1 (en) * | 2008-06-27 | 2009-12-31 | Academia Sinica | Immunogenic Protein Carrier Containing An Antigen Presenting Cell Binding Domain and A Cysteine-Rich Domain |
Non-Patent Citations (10)
Title |
---|
BRITISH J. CANCER, vol. 100, 2009, pages 1746 - 1754 |
CARBOHYDR. RES., vol. 253, 1994, pages 167 - 183 |
J. ORG. CHEM., vol. 65, 2000, pages 144 - 151 |
MONATSHEFTE FUER CHEMIE., vol. 133, 2002, pages 531 - 540 |
REDDISH MARK A. ET AL.: "Specificities of anti-sialyl-Tn and anti-Tn monoclonal antibodies generated using novel clustered synthetic glycopeptide epitopes", GLYCOCONJUGATE JOURNAL, vol. 14, no. 5, 1997, pages 549 - 560, XP002415009 * |
SAHABUDDIN SK ET AL., SYNTHESIS OF N-MODIFIED STN ANALOGS AND EVALUATION OF HEIR IMMUNOGENICITIES BY MICROARRAY-BASED IMMUNOASSAY, vol. 66, no. 38, 18 September 2010 (2010-09-18), pages 7510 - 7519, XP027231283 * |
See also references of EP2581380A4 |
TETRAHEDRON LETT., vol. 33, 1992, pages 6123 - 6126 |
TETRAHEDRON LETT., vol. 46, 2005, pages 8993 - 8995 |
YANG FAN ET AL.: "Enhancement of the Immunogenicity of Synthetic Carbohydrate Vaccines by Chemical Modifications of STn Antigen", ACS CHEMICAL BIOLOGY, vol. 6, no. 3, 18 March 2011 (2011-03-18), pages 252 - 259, XP009173423, DOI: doi:10.1021/cb100287q * |
Also Published As
Publication number | Publication date |
---|---|
JP2013532135A (ja) | 2013-08-15 |
US20130079291A1 (en) | 2013-03-28 |
EP2581380A1 (en) | 2013-04-17 |
CN102276662B (zh) | 2014-05-14 |
EP2581380B1 (en) | 2017-06-07 |
US9695208B2 (en) | 2017-07-04 |
JP5815687B2 (ja) | 2015-11-17 |
CN102276662A (zh) | 2011-12-14 |
EP2581380A4 (en) | 2013-11-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7854934B2 (en) | Glycoconjugates, glycoamino acids, intermediates thereto, and uses thereof | |
US8623378B2 (en) | Glycoconjugates, glycoamino acids, intermediates thereto, and uses thereof | |
FI64164B (fi) | Foerfarande foer framstaellning av 2-(2-acylamino-2-desoxi-(d)-glukosyl-3-0)-alkankarboxylsyrapeptid-derivat | |
ES2256857T3 (es) | Sintesis del antigeno asociado al tumor de mama definido por el anticuerpo monoclonal mbr1 y sus usos. | |
Allen et al. | A second generation synthesis of the MBr1 (Globo‐H) breast tumor antigen: New application of the N‐pentenyl glycoside method for achieving complex carbohydrate protein linkages | |
CA2227592A1 (en) | Synthesis of glycoconjugates of the lewis y epitope and uses thereof | |
JP2016530212A (ja) | ストレプトコッカス ニューモニエ3型に対するタンパク質およびペプチドフリーの合成ワクチン | |
JP2021504439A (ja) | クレブシエラ ニューモニエ(Klebsiella pneumoniae)に対するワクチン | |
JP6416249B2 (ja) | ストレプトコッカス ニューモニエ1型に対する合成ワクチン | |
WO2011153815A1 (zh) | 唾液酸(α-(2→6))-D-吡喃糖衍生物及其合成方法和应用 | |
CN107709343B (zh) | 针对肺炎链球菌血清型5的疫苗 | |
Lockhoff et al. | Syntheses of glycosylamides as glycolipid analogs | |
JPWO2016104647A1 (ja) | 糖鎖結合ワクチン抗原及び糖鎖導入剤 | |
US20080213297A1 (en) | Method of producing conjugate vaccines | |
WO1993000908A1 (en) | Elam-1 receptor ligands as diagnostic compounds | |
US20210260204A1 (en) | Fluoro-tf-muc1 glycopeptide conjugate, preparation method and application thereof | |
CN106084037B (zh) | 一种炭疽杆菌荚膜表面三糖缀合物及其制备方法和应用 | |
JP2011032180A (ja) | Cd22分子に対する高親和性を有しb細胞の増殖を増強する化合物 | |
Miranda et al. | Bifunctional compound and its use in immunotherapy | |
CN115779075A (zh) | 一种单磷酸类酯A(MPLA)缀合糖抗原STn抗肿瘤疫苗及其应用 | |
JP4721571B2 (ja) | 非ムチン型合成化合物−担体結合物 | |
EP3000820A1 (en) | Synthetic vaccines against Streptococcus pneumoniae serotype 8 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11791807 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013512727 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13703007 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2011791807 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011791807 Country of ref document: EP |